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Gu Q, Zou J, Zhou Y, Deng Q. Mechanism of inflammasomes in cancer and targeted therapies. Front Oncol 2023; 13:1133013. [PMID: 37020871 PMCID: PMC10067570 DOI: 10.3389/fonc.2023.1133013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 03/06/2023] [Indexed: 03/22/2023] Open
Abstract
Inflammasomes, composed of the nucleotide-binding oligomerization domain(NOD)-like receptors (NLRs), are immune-functional protein multimers that are closely linked to the host defense mechanism. When NLRs sense pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), they assemble into inflammasomes. Inflammasomes can activate various inflammatory signaling pathways, including nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, and produce a large number of proinflammatory cytokines, which are closely associated with multiple cancers. They can also accelerate the occurrence and development of cancer by providing suitable tumor microenvironments, promoting tumor cell proliferation, and inhibiting tumor cell apoptosis. Therefore, the exploitation of novel targeted drugs against various inflammasomes and proinflammatory cytokines is a new idea for the treatment of cancer. In recent years, more than 50 natural extracts and synthetic small molecule targeted drugs have been reported to be in the research stage or have been applied to the clinic. Herein, we will overview the mechanisms of inflammasomes in common cancers and discuss the therapeutic prospects of natural extracts and synthetic targeted agents.
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Affiliation(s)
- Qingdan Gu
- Department of Clinical Laboratory, Shenzhen Longhua District Central Hospital, Guangdong Medical University, Shenzhen, Guangdong, China
| | - Jiazhen Zou
- Department of Laboratory Medicine, Shenzhen Second People’s Hospital, The First Affiliated 5 Hospital of Shenzhen University, Health Science Center, Shenzhen, China
| | - Ying Zhou
- Department of Clinical Laboratory, Shenzhen Longhua District Central Hospital, Guangdong Medical University, Shenzhen, Guangdong, China
| | - Qiuchan Deng
- Department of Clinical Laboratory, Shenzhen Longhua District Central Hospital, Guangdong Medical University, Shenzhen, Guangdong, China
- *Correspondence: Qiuchan Deng,
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2
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Sobotka LA, Mumtaz K, Wellner MR, Kelly SG, Conteh LF, Hanje AJ, Schenk A, El-Hinnawi A, Black S, Washburn K, Pesavento T, Daloul R, Michaels AJ. Outcomes of hepatitis C virus seropositive donors to hepatitis C virus seronegative liver recipients: A large single center analysis. Ann Hepatol 2022; 24:100318. [PMID: 33515801 DOI: 10.1016/j.aohep.2021.100318] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/18/2020] [Accepted: 01/04/2021] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES The success of direct-acting antivirals (DAA) has transformed the management of hepatitis C virus (HCV) infection and has led to the expansion of the deceased donor organ pool for liver transplantation. MATERIAL AND METHODS We present a single center retrospective review of liver transplantations performed on HCV-seronegative recipients from HCV-seropositive organs from 11/2017 to 05/2020. HCV nucleic acid testing (NAT) was performed on HCV-seropositive donors to assess active HCV infection. RESULTS 42 HCV-seronegative recipients underwent a liver transplant from a HCV-seropositive donor, including 21 NAT negative (20 liver, 1 simultaneous liver kidney transplant) and 21 NAT positive liver transplants. Two (9.5%) HCV antibody positive/NAT negative recipients developed HCV viremia and achieved sustained virologic response with DAA therapy. The remaining patients with available data (19 patients) remained polymerase chain reaction (PCR) negative at 6 months. 20 (95%) of HCV antibody positive/NAT positive recipients had a confirmed HCV viremia. 100% of patients with available data (15 patients) achieved SVR. Observed events include 1 mortality and graft loss and equivalent rates of post-transplant complications between NAT positive and NAT negative recipients. CONCLUSIONS HCV-seropositive organs can be safely transplanted into HCV-seronegative patients with minimal complications post-transplant.
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Affiliation(s)
- Lindsay A Sobotka
- Division of Internal Medicine, Department of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Columbus OH, USA
| | - Khalid Mumtaz
- Division of Internal Medicine, Department of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Columbus OH, USA
| | - Michael R Wellner
- Division of Internal Medicine, Department of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Columbus OH, USA
| | - Sean G Kelly
- Division of Internal Medicine, Department of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Columbus OH, USA
| | - Lanla F Conteh
- Division of Internal Medicine, Department of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Columbus OH, USA
| | - A James Hanje
- Division of Internal Medicine, Department of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Columbus OH, USA
| | - Austin Schenk
- Division of Surgery, Department of Transplantation, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Ashraf El-Hinnawi
- Division of Surgery, Department of Transplantation, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Sylvester Black
- Division of Surgery, Department of Transplantation, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Kenneth Washburn
- Division of Surgery, Department of Transplantation, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Todd Pesavento
- Division of Internal Medicine, Department of Nephrology, The Ohio State University Wexner Medical Center, Columbus OH, USA
| | - Reem Daloul
- Division of Internal Medicine, Department of Nephrology, The Ohio State University Wexner Medical Center, Columbus OH, USA
| | - Anthony J Michaels
- Division of Internal Medicine, Department of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Columbus OH, USA.
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Ismail MS, Mohamed I, Polychronopoulou E, Goss JA, Kuo YF, Kanwal F, Jalal PK. Outcomes in the Era of Interferon-Free Direct-Acting Antiviral Therapy After Liver Transplantation in Patients with Hepatitis C Virus and Hepatocellular Carcinoma. J Hepatocell Carcinoma 2021; 8:701-711. [PMID: 34235107 PMCID: PMC8254565 DOI: 10.2147/jhc.s309354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 06/02/2021] [Indexed: 11/23/2022] Open
Abstract
Background/Aims Several studies have shown improved outcome of liver transplant (LT) recipients with hepatitis C virus (HCV) since the widespread clinical use of interferon-free direct-acting antivirals (IFN-free DAAs). However, the association of IFN-free DAA therapy on tumor characteristics and on the outcome of LT in patients with hepatocellular carcinoma (HCC) has not been studied. We aimed to examine pre-transplant HCC characteristics and post-LT outcomes in the IFN-based DAA treatment and IFN-free DAA treatment eras. Methods Using the United Network for Organ Sharing/Organ Procurement and Transplantation Network database, we analyzed adults with a diagnosis of HCV and HCC who received LTs from deceased donors from 04/2012 to 12/2017. Cox regression models were used to identify the association between the IFN-based DAA treatment vs IFN-free DAA treatment era and study outcomes (mortality, graft failure, and HCC recurrence at 1 and 3 years). Results Complete tumor necrosis was significantly higher in the IFN-free DAA treatment era (22.73% vs 18.22%; P <0.01). No other HCC tumor characteristics differed significantly between the two eras. HCC recurrence rates were similar between the two eras. On multivariate Cox regression analysis, patients who had transplants in the IFN-free DAA treatment era had lower risk of graft failure compared with the IFN-based DAA treatment group (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.25–0.77; P <0.01). Patient mortality was lower in the IFN-free DAA treatment era although the difference was not statistically significant (HR, 0.82; 95% CI, 0.60–1.13; P =0.22). Conclusion LT recipients in the IFN-free DAA treatment era had significantly higher complete tumor necrosis in explants. Other HCC tumor characteristics were similar between the two eras. Post-LT graft failure at 1 and 3 years significantly decreased in the IFN-free DAA treatment era among patients with HCV and HCC, although patient mortality was not statistically different.
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Affiliation(s)
- Mohamed Saleh Ismail
- Division of Gastroenterology, Baylor College of Medicine, Houston, TX, USA.,Department of Internal Medicine, Gastroenterology & Hepatology, Ain Shams University, Cairo, Egypt
| | - Islam Mohamed
- Division of Gastroenterology, Baylor College of Medicine, Houston, TX, USA.,Department of Internal Medicine, Gastroenterology & Hepatology, Ain Shams University, Cairo, Egypt
| | | | - John A Goss
- Michael E. DeBakey Department of Surgery, Division of Abdominal Transplantation, Baylor College of Medicine, Houston, TX, USA
| | - Yong-Fang Kuo
- Department of Biostatistics, The University of Texas Medical Branch, Galveston, TX, USA
| | - Fasiha Kanwal
- Division of Gastroenterology, Baylor College of Medicine, Houston, TX, USA
| | - Prasun K Jalal
- Division of Gastroenterology, Baylor College of Medicine, Houston, TX, USA.,Michael E. DeBakey Department of Surgery, Division of Abdominal Transplantation, Baylor College of Medicine, Houston, TX, USA
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Khan AS, Adams N, Vachharajani N, Dageforde L, Wellen J, Shenoy S, Crippin JS, Doyle MB, Chapman WC. Liver transplantation for hepatitis C patients in the era of direct-acting antiviral treatment: A retrospective cohort study. Int J Surg 2020; 75:84-90. [PMID: 32014598 DOI: 10.1016/j.ijsu.2020.01.145] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 01/10/2020] [Accepted: 01/23/2020] [Indexed: 12/27/2022]
Abstract
INTRODUCTION Direct-acting antivirals (DAA's) have revolutionized hepatitis-C virus (HCV) treatment, however controversy remains regarding timing of treatment in relation to liver-transplant (LT). METHODS Single-center retrospective study assessing outcomes of listed HCV positive patients in the DAA-era (2014-2017). Patients treated with DAA's before LT (DAA pre-LT) were compared to those who were not treated before LT (No DAA pre-LT) RESULTS: 156 HCV positive patients were listed during study-period; 104 (67%) underwent LT while 52 (33%) were de-listed. Of transplanted patients, 48 (46%) received DAA pre-LT while 56 (54%) were treated post-LT. Both groups were comparable in age, gender, MELD, patient and graft survival and cure-rates (98% in DAA pre-LTvs.95% in No DAA pre-LT; p > 0.05). DAA pre-LT group required higher number of treatments-per-patient to clear virus (1.46vs.1.06; p = 0.0006), spent more time on waitlist (331d.vs150d; p = 0.0040) and were less likely to receive livers from HCV positive donors (6%vs.25%; p = 0.0148). Twenty-nine (56%) of the 52 delisted received DAA. They had lower listing-MELD (12vs.18; p = 0.0033), and were more likely to be delisted for "condition improved" (34%vs.4%; p = 0.0143) compared to the 23 (44%) delisted patients who did not receive DAA's. CONCLUSIONS DAA's were equally effective in clearing HCV in listed patients irrespective of timing. DAA pre-LT can disadvantage some patients through increase number of treatments needed and longer waitlist times, but treatment in some listed patients with low-MELD can improve condition and alleviate need for LT.
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Affiliation(s)
- Adeel S Khan
- Section of Transplant Surgery, Washington University St. Louis, One Barnes-Jewish Hospital Plaza, Suite 6107 Queeny Tower, St Louis, MO, 63110, USA.
| | - Nathaniel Adams
- Section of Transplant Surgery, Washington University St. Louis, One Barnes-Jewish Hospital Plaza, Suite 6107 Queeny Tower, St Louis, MO, 63110, USA.
| | - Neeta Vachharajani
- Section of Transplant Surgery, Washington University St. Louis, One Barnes-Jewish Hospital Plaza, Suite 6107 Queeny Tower, St Louis, MO, 63110, USA.
| | - LeighAnne Dageforde
- Section of Transplant Surgery, Washington University St. Louis, One Barnes-Jewish Hospital Plaza, Suite 6107 Queeny Tower, St Louis, MO, 63110, USA.
| | - Jason Wellen
- Section of Transplant Surgery, Washington University St. Louis, One Barnes-Jewish Hospital Plaza, Suite 6107 Queeny Tower, St Louis, MO, 63110, USA.
| | - Surendra Shenoy
- Section of Transplant Surgery, Washington University St. Louis, One Barnes-Jewish Hospital Plaza, Suite 6107 Queeny Tower, St Louis, MO, 63110, USA.
| | - Jeffrey S Crippin
- Department of Medicine, Washington University St. Louis, One Barnes-Jewish Hospital Plaza, Suite 6107 Queeny Tower, St Louis, MO, 63110, USA.
| | - Majella B Doyle
- Section of Transplant Surgery, Washington University St. Louis, One Barnes-Jewish Hospital Plaza, Suite 6107 Queeny Tower, St Louis, MO, 63110, USA.
| | - William C Chapman
- Section of Transplant Surgery, Washington University St. Louis, One Barnes-Jewish Hospital Plaza, Suite 6107 Queeny Tower, St Louis, MO, 63110, USA.
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Udden SN, Kwak YT, Godfrey V, Khan MAW, Khan S, Loof N, Peng L, Zhu H, Zaki H. NLRP12 suppresses hepatocellular carcinoma via downregulation of cJun N-terminal kinase activation in the hepatocyte. eLife 2019; 8:40396. [PMID: 30990169 PMCID: PMC6483596 DOI: 10.7554/elife.40396] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 03/25/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a deadly human cancer associated with chronic inflammation. The cytosolic pathogen sensor NLRP12 has emerged as a negative regulator of inflammation, but its role in HCC is unknown. Here we investigated the role of NLRP12 in HCC using mouse models of HCC induced by carcinogen diethylnitrosamine (DEN). Nlrp12-/- mice were highly susceptible to DEN-induced HCC with increased inflammation, hepatocyte proliferation, and tumor burden. Consistently, Nlrp12-/- tumors showed higher expression of proto-oncogenes cJun and cMyc and downregulation of tumor suppressor p21. Interestingly, antibiotics treatment dramatically diminished tumorigenesis in Nlrp12-/- mouse livers. Signaling analyses demonstrated higher JNK activation in Nlrp12-/- HCC and cultured hepatocytes during stimulation with microbial pattern molecules. JNK inhibition or NLRP12 overexpression reduced proliferative and inflammatory responses of Nlrp12-/- hepatocytes. In summary, NLRP12 negatively regulates HCC pathogenesis via downregulation of JNK-dependent inflammation and proliferation of hepatocytes.
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Affiliation(s)
- Sm Nashir Udden
- Department of Pathology, UT Southwestern Medical Center, Dallas, United States
| | - Youn-Tae Kwak
- Department of Pathology, UT Southwestern Medical Center, Dallas, United States.,Department of Biochemistry, UT Southwestern Medical Center, Dallas, United States
| | - Victoria Godfrey
- Department of Pathology, UT Southwestern Medical Center, Dallas, United States
| | - Md Abdul Wadud Khan
- Department of Surgical Oncology, MD Anderson Cancer Center, Houston, United States
| | - Shahanshah Khan
- Department of Pathology, UT Southwestern Medical Center, Dallas, United States
| | - Nicolas Loof
- Children's Research Institute, UT Southwestern Medical Center, Dallas, United States
| | - Lan Peng
- Department of Pathology, UT Southwestern Medical Center, Dallas, United States
| | - Hao Zhu
- Children's Research Institute, UT Southwestern Medical Center, Dallas, United States.,Department of Pediatrics, UT Southwestern Medical Center, Dallas, United States.,Center for Regenerative Science and Medicine, UT Southwestern Medical Center, Dallas, United States.,Department of Internal Medicine, UT Southwestern Medical Center, Dallas, United States
| | - Hasan Zaki
- Department of Pathology, UT Southwestern Medical Center, Dallas, United States
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Axelrod DA, Schnitzler MA, Alhamad T, Gordon F, Bloom RD, Hess GP, Xiao H, Nazzal M, Segev DL, Dharnidharka VR, Naik AS, Lam NN, Ouseph R, Kasiske BL, Durand CM, Lentine KL. The impact of direct-acting antiviral agents on liver and kidney transplant costs and outcomes. Am J Transplant 2018; 18:2473-2482. [PMID: 29701909 PMCID: PMC6409105 DOI: 10.1111/ajt.14895] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 04/14/2018] [Accepted: 04/17/2018] [Indexed: 02/06/2023]
Abstract
Direct-acting antiviral medications (DAAs) have revolutionized care for hepatitis C positive (HCV+) liver (LT) and kidney (KT) transplant recipients. Scientific Registry of Transplant Recipients registry data were integrated with national pharmaceutical claims (2007-2016) to identify HCV treatments before January 2014 (pre-DAA) and after (post-DAA), stratified by donor (D) and recipient (R) serostatus and payer. Pre-DAA, 18% of HCV+ LT recipients were treated within 3 years and without differences by donor serostatus or payer. Post-DAA, only 6% of D-/R+ recipients, 19.8% of D+/R+ recipients with public insurance, and 11.3% with private insurance were treated within 3 years (P < .0001). LT recipients treated for HCV pre-DAA experienced higher rates of graft loss (adjusted hazard ratio [aHR] 1.34 1.852.10 , P < .0001) and death (aHR 1.47 1.681.91 , P < .0001). Post-DAA, HCV treatment was not associated with death (aHR 0.34 0.671.32 , P = .25) or graft failure (aHR 0.32 0.641.26 , P = .20) in D+R+ LT recipients. Treatment increased in D+R+ KT recipients (5.5% pre-DAA vs 12.9% post-DAA), but did not differ by payer status. DAAs reduced the risk of death after D+/R+ KT by 57% (0.19 0.430.95 , P = .04) and graft loss by 46% (0.27 0.541.07 , P = .08). HCV treatment with DAAs appears to improve HCV+ LT and KT outcomes; however, access to these medications appears limited in both LT and KT recipients.
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Affiliation(s)
- D A Axelrod
- Lahey Hospital & Medical Center, Burlington, MA, USA
| | - M A Schnitzler
- Saint Louis University Center for Abdominal Transplantation, St. Louis, MO, USA
| | - T Alhamad
- Washington University, St. Louis, MO, USA
| | - F Gordon
- Lahey Hospital & Medical Center, Burlington, MA, USA
| | - R D Bloom
- University of Pennsylvania, Philadelphia, PA, USA
| | - G P Hess
- Symphony Health, Conshohocken, PA, USA
| | - H Xiao
- Saint Louis University Center for Abdominal Transplantation, St. Louis, MO, USA
| | - M Nazzal
- Saint Louis University Center for Abdominal Transplantation, St. Louis, MO, USA
| | - D L Segev
- Johns Hopkins University, Baltimore, MD, USA
| | | | - A S Naik
- University of Michigan, Ann Arbor, MI, USA
| | - N N Lam
- University of Alberta, Edmonton, AB, Canada
| | - R Ouseph
- Saint Louis University Center for Abdominal Transplantation, St. Louis, MO, USA
| | - B L Kasiske
- Hennepin County Medical Center, Minneapolis, MN, USA
| | - C M Durand
- Johns Hopkins University, Baltimore, MD, USA
| | - K L Lentine
- Saint Louis University Center for Abdominal Transplantation, St. Louis, MO, USA
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Crespo G, Trota N, Londoño MC, Mauro E, Baliellas C, Castells L, Castellote J, Tort J, Forns X, Navasa M. The efficacy of direct anti-HCV drugs improves early post-liver transplant survival and induces significant changes in waiting list composition. J Hepatol 2018; 69:11-17. [PMID: 29481821 DOI: 10.1016/j.jhep.2018.02.012] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Revised: 02/01/2018] [Accepted: 02/11/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS The efficacy of direct-acting antivirals (DAAs) has dramatically changed the prognosis of patients with chronic hepatitis C. We aimed to evaluate the impact of DAA therapy on the composition of the liver transplant (LT) waiting list and the early post-transplant survival. METHODS We evaluated all patients admitted to the waiting list for a primary LT between 1st January 2008 and 31st of December 2016 in Catalonia, Spain. Time span was divided into two periods according to the availability of different antiviral therapies: 2008-2013 (interferon-based therapies) and 2014-2016 (DAA). Changes in the indications of LT and the aetiology of liver disease, as well as post-LT patient survival, were evaluated according to the year of inclusion and transplantation, respectively. RESULTS We included 1,483 patients. Admissions in the waiting list for hepatitis C virus (HCV)-related liver disease decreased significantly, from 47% in 2008-2013 to 35% in 2014-2016 (p <0.001), particularly because of a reduction in patients with decompensated cirrhosis. In contrast, NASH-related inclusions increased from 4% to 7% (p = 0.003). Three-year post-LT patient survival increased significantly in the second period in the whole cohort (82% vs. 91%, p = 0.002), because of better survival in anti-HCV positive patients (76% vs. 91%, p = 0.001), but not in anti-HCV negative patients (88% vs. 91% p = 0.359). Anti-HCV positive serology, the time period of 2008-2013 and higher donor age were independently associated with post-LT mortality in the whole cohort; while time period and donor age were independently associated with post-LT mortality in anti-HCV positive recipients. CONCLUSIONS The high efficacy of DAAs is associated with significant changes in the composition of the LT waiting list and, more importantly, results in improved post-transplant survival. LAY SUMMARY The efficacy of the new direct-acting antivirals is associated with a significant improvement in survival of patients undergoing liver transplantation because of hepatitis C virus-related liver disease. In addition, it has decreased the number of patients with hepatitis C that need a liver transplant.
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Affiliation(s)
- Gonzalo Crespo
- Liver Transplant Unit, Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, Universitat de Barcelona, Spain.
| | - Núria Trota
- Organització Catalana de Trasplantaments, Servei Català de la Salut, Catalonia, Spain
| | | | - Ezequiel Mauro
- Liver Transplant Unit, Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, Universitat de Barcelona, Spain; Liver Unit, Hospital Italiano, Buenos Aires, Argentina
| | - Carme Baliellas
- Liver Transplant Unit, Liver Unit, Hospital Universitari de Bellvitge, IDIBELL, Universitat de Barcelona, Spain
| | - Lluís Castells
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, CIBERehd, Spain
| | - Jose Castellote
- Liver Transplant Unit, Liver Unit, Hospital Universitari de Bellvitge, IDIBELL, Universitat de Barcelona, Spain
| | - Jaume Tort
- Organització Catalana de Trasplantaments, Servei Català de la Salut, Catalonia, Spain
| | - Xavier Forns
- Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, Universitat de Barcelona, Spain
| | - Miquel Navasa
- Liver Transplant Unit, Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, Universitat de Barcelona, Spain
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Ramadori G, Bosio P, Moriconi F, Malik IA. Case report: 8 years after liver transplantation: de novo hepatocellular carcinoma 8 months after HCV clearance through IFN-free antiviral therapy. BMC Cancer 2018; 18:257. [PMID: 29510685 PMCID: PMC5840818 DOI: 10.1186/s12885-018-4175-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Accepted: 03/01/2018] [Indexed: 12/14/2022] Open
Abstract
Background After orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC), recurrent HCC mostly develops within 2 years. All cases of de novo HCC described so far occurred later than 2 years after OLT. Prevention of post-transplantation HCC has usually been tried to achieve by curing or controlling recurrent liver disease. This has been rationale for treatment with interferon (IFN)/ribavirin of HCV-recurrence in patients after OLT, transplanted for advanced HCV-induced liver disease and/or HCC. The availability of new and more efficient drugs has improved chances also for previously difficult-to-treat HCV-positive patients. Case presentation A 75 year-old male patient who had undergone OLT for decompensated HCV-cirrhosis in 2009, and bilio-digestive surgery in 2011 under tracrolimus (0.5 mg/day) and prednisone (5 mg/day) immunosuppressive therapy, started to receive antiviral treatment for recurrent HCV-infection of graft with 200 mg/day ribavirin in combination with ledipasvir and sofosbuvir by the end of October 2015. Because of multiple side effects (anemia, asthenia, infections, and reduction of kidney functions - palliated by treatment with erythropoietin), treatment was stopped after 16 weeks. At the third control, a minimal increase in alpha-fetoprotein (AFP) serum level to 10 μg/L was measured 8 months after therapy, whereas both liver sonography and serum transaminases were normal. The patient’s general condition; however, remained poor, and a magnetic resonance imaging (MRI) of abdomen was performed 2 months later. A nodule of 3 cm in diameter with a pseudocapsule was found centrally in the liver. The patient had to be hospitalized for recurrent infections of the lung, overt ascites and peritonitis. Rapid tumor growth (10 cm) was detected during last stay in hospital (April 2017), concomitant with a rise of AFP-serum levels to 91 μg/L. The family decided to take the patient home, and best supportive care was provided by a general practitioner, local nurses and the patient’s dedicated wife until his death. Conclusion Before treating OLT patients with HCV graft reinfection one should not only consider possible advantages of newly effective antiviral-therapies, but also life expectancy and possible side effects (difficult to manage at an outpatient service basis), including severe disadvantages such as the development of HCC.
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Affiliation(s)
- Giuliano Ramadori
- Department of Gastroenterology and Endocrinology, University Medical Center Goettingen, Robert-Koch-Street 40, D-37075, Goettingen, Germany.
| | - Patrizia Bosio
- General Practitioner, National health care system, Palazzago, BG, Italy
| | | | - Ihtzaz A Malik
- Institute of Anatomy and Cell Biology, University Medical Center, Kreuzbering 36, 37075, Goettingen, Germany
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9
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International Liver Transplantation Society Consensus Statement on Hepatitis C Management in Liver Transplant Candidates. Transplantation 2018; 101:945-955. [PMID: 28437387 DOI: 10.1097/tp.0000000000001708] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Gadiparthi C, Cholankeril G, Perumpail BJ, Yoo ER, Satapathy SK, Nair S, Ahmed A. Use of direct-acting antiviral agents in hepatitis C virus-infected liver transplant candidates. World J Gastroenterol 2018; 24:315-322. [PMID: 29391754 PMCID: PMC5776393 DOI: 10.3748/wjg.v24.i3.315] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 12/05/2017] [Accepted: 12/12/2017] [Indexed: 02/06/2023] Open
Abstract
Since the advent of direct acting antiviral (DAA) agents, chronic hepatitis C virus (HCV) treatment has evolved at a rapid pace. In contrast to prior regimen involving ribavirin and pegylated interferon, these newer agents are highly effective, well-tolerated, have shorter course of therapy and safer essentially in all HCV patients including those with advanced liver disease and following liver transplantation. Clinicians caring for HCV-infected patients on the liver transplant (LT) waitlist are often faced with a dilemma whether to treat HCV infection before or after liver transplantation. Sustained virological response (SVR) rates following HCV treatment may improve hepatic function sufficiently enough to negate the need for LT in certain patients. On the other hand, the decrease in MELD without improvement in quality of life in certain patients may lead to delay or dropout from potentially curative LT surgery list. In this context, our review focuses on the approach to and optimal timing of DAA-based treatment of HCV infection in LT candidates in the peri-transplant period.
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Affiliation(s)
- Chiranjeevi Gadiparthi
- Division of Gastroenterology and Hepatology, University of Tennessee Health Sciences Center, Memphis, TN 38104, United States
| | - George Cholankeril
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA 94304, United States
| | - Brandon J Perumpail
- Drexel University College of Medicine, Philadelphia, PA 19129, United States
| | - Eric R Yoo
- Department of Medicine, Santa Clara Valley Medical Center, San Jose, CA 95128, United States
| | - Sanjaya K Satapathy
- Division of Gastroenterology and Hepatology, University of Tennessee Health Sciences Center, Memphis, TN 38104, United States
| | - Satheesh Nair
- Division of Gastroenterology and Hepatology, University of Tennessee Health Sciences Center, Memphis, TN 38104, United States
| | - Aijaz Ahmed
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA 94304, United States
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Saxena V, Terrault NA. Recurrent Primary Disease After Liver Transplantation. ZAKIM AND BOYER'S HEPATOLOGY 2018:784-815.e14. [DOI: 10.1016/b978-0-323-37591-7.00053-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Cholankeril G, Joseph-Talreja M, Perumpail BJ, Liu A, Yoo ER, Ahmed A, Goel A. Timing of Hepatitis C Virus Treatment in Liver Transplant Candidates in the Era of Direct-acting Antiviral Agents. J Clin Transl Hepatol 2017; 5:363-367. [PMID: 29226102 PMCID: PMC5719193 DOI: 10.14218/jcth.2017.00007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Revised: 07/30/2017] [Accepted: 08/18/2017] [Indexed: 12/16/2022] Open
Abstract
Chronic hepatitis C virus (HCV) infection remains the leading indication for liver transplantation (LT) in the United States. While most patients with chronic HCV infection remain asymptomatic, up to one-third develop progressive liver disease resulting in cirrhosis. LT is often the only curative treatment once significant hepatic decompensation develops. However, antiviral therapy for HCV infection has advanced markedly in the past 5 years with the discovery and approval of direct-acting antiviral agents. These new regimens are well tolerated, of short duration and highly effective, unlike the traditional treatment with pegylated-interferon and ribavirin. As achieving sustained virological response becomes increasingly attainable for a majority of HCV-infected patients, concerns have been raised regarding the optimal timing of treatment for HCV infection in the setting of end-stage liver disease and during the peri-transplant period. On one hand, HCV treatment may improve hepatic function and negate the need for LT in some, which is crucial given the scarcity of donor organs and mortality on the waiting list in certain regions. On the other hand, HCV treatment may result in lowering the priority for LT without improving quality of life, thereby delaying potentially curative LT surgery. This review evaluates the evidence supporting the use of direct-acting antiviral agents in the period before and following LT.
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Affiliation(s)
- George Cholankeril
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| | - Mairin Joseph-Talreja
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| | - Brandon J. Perumpail
- Department of Medicine, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Andy Liu
- Department of Medicine, California Pacific Medical Center, San Francisco, CA, USA
| | - Eric R. Yoo
- Department of Medicine, Santa Clara Valley Medical Center, San Jose, CA, USA
| | - Aijaz Ahmed
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
- *Correspondence to: Aijaz Ahmed, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, 750 Welch Road, Suite #210, Stanford, CA 94304, USA. Tel: +1-650-498-6091, Fax: +1-650-498-5692, E-mail:
| | - Aparna Goel
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
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Pascasio JM, Vinaixa C, Ferrer MT, Colmenero J, Rubin A, Castells L, Manzano ML, Lorente S, Testillano M, Xiol X, Molina E, González-Diéguez L, Otón E, Pascual S, Santos B, Herrero JI, Salcedo M, Montero JL, Sánchez-Antolín G, Narváez I, Nogueras F, Giráldez Á, Prieto M, Forns X, Londoño MC. Clinical outcomes of patients undergoing antiviral therapy while awaiting liver transplantation. J Hepatol 2017; 67:1168-1176. [PMID: 28842296 DOI: 10.1016/j.jhep.2017.08.008] [Citation(s) in RCA: 93] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 08/09/2017] [Accepted: 08/09/2017] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Antiviral therapy for the treatment of hepatitis C (HCV) infection has proved to be safe and efficacious in patients with cirrhosis awaiting liver transplantation (LT). However, the information regarding the clinical impact of viral eradication in patients on the waiting list is still limited. The aim of the study was to investigate the probability of delisting in patients who underwent antiviral therapy, and the clinical outcomes of these delisted patients. METHODS Observational, multicenter and retrospective analysis was carried out on prospectively collected data from patients positive for HCV, treated with an interferon-free regimen, while awaiting LT in 18 hospitals in Spain. RESULTS In total, 238 patients were enrolled in the study. The indication for LT was decompensated cirrhosis (with or without hepatocellular carcinoma [HCC]) in 171 (72%) patients, and HCC in 67 (28%) patients. Sustained virologic response (SVR) rate was significantly higher in patients with compensated cirrhosis and HCC (92% vs. 83% in patients with decompensated cirrhosis with or without HCC, p=0.042). Among 122 patients with decompensated cirrhosis without HCC, 29 (24%) were delisted due to improvement. No patient with baseline MELD score >20 was delisted. After delisting (median follow-up of 88weeks), three patients had clinical decompensations and three had de novo HCC. Only two of the patients with HCC had to be re-admitted onto the waiting list. The remaining 23 patients remained stable, with no indication for LT. CONCLUSIONS Antiviral therapy is safe and efficacious in patients awaiting LT. A quarter of patients with decompensated cirrhosis can be delisted asa result of clinical improvement, which appears to be remain stable in most patients. Thus, delisting is a safe strategy that could spare organs and benefit other patients with a more urgent need. LAY SUMMARY Antiviral therapy in patients awaiting liver transplantation is safe and efficacious. Viral eradication allows removal from the waiting list of a quarter of treated patients. Delisting because of clinical improvement is a safe strategy that can spare organs for patients in urgent need.
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Affiliation(s)
- Juan Manuel Pascasio
- UGC Digestive Diseases, Hospital Universitario Virgen del Rocío, IBIS, CIBERehd, Sevilla, Spain
| | - Carmen Vinaixa
- Liver Unit, Digestive Medicine Service, Hospital Universitario La Fé, CIBERehd, Valencia, Spain
| | - María Teresa Ferrer
- UGC Digestive Diseases, Hospital Universitario Virgen del Rocío, IBIS, CIBERehd, Sevilla, Spain
| | - Jordi Colmenero
- Liver Unit, Hospital Clinic, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Angel Rubin
- Liver Unit, Digestive Medicine Service, Hospital Universitario La Fé, CIBERehd, Valencia, Spain
| | - Lluis Castells
- Internal Medicine Service, Hospital Universitari Vall d'Hebron, CIBERehd, Barcelona, Spain
| | - María Luisa Manzano
- Digestive Diseases Service, Hospital Universitario 12 Octubre, Madrid, Spain
| | - Sara Lorente
- Liver Transplant Unit, Digestive Diseases Service, Hospital Universitario Lozano Blesa, Zaragoza, Spain
| | - Milagros Testillano
- Liver Unit, Digestive Diseases Service, Hospital Universitario Cruces, Vizcaya, Spain
| | - Xavier Xiol
- Digestive Diseases Service, Hospital Universitari Bellvitge, Barcelona, Spain
| | - Esther Molina
- Abdominal Transplant Unit, CHU Santiago de Compostela, IDIS, Santiago, Spain
| | | | - Elena Otón
- Digestive Diseases Service, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, Spain
| | - Sonia Pascual
- Liver Unit, Hospital General Universitario, CIBERehd, Alicante, Spain
| | - Begoña Santos
- Internal Medicine Service, Hospital Universitari Vall d'Hebron, CIBERehd, Barcelona, Spain
| | | | - Magdalena Salcedo
- Liver Transplant Unit, Hospital General Universitario Gregorio Marañón, CIBERehd, Madrid, Spain
| | - José Luis Montero
- UGC Aparato Digestivo, Hospital Universitario Reina Sofía, Córdoba, Spain
| | | | - Isidoro Narváez
- Digestive Diseases Service, Hospital Universitario Infanta Cristina, Badajoz, Spain
| | - Flor Nogueras
- Digestive Diseases Service, Hospital Universitario Virgen de las Nieves, Granada, Spain
| | - Álvaro Giráldez
- UGC Digestive Diseases, Hospital Universitario Virgen del Rocío, IBIS, CIBERehd, Sevilla, Spain
| | - Martín Prieto
- Liver Unit, Digestive Medicine Service, Hospital Universitario La Fé, CIBERehd, Valencia, Spain
| | - Xavier Forns
- Liver Unit, Hospital Clinic, IDIBAPS, CIBERehd, Barcelona, Spain
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Quader M, Wolfe LG, Katlaps G, Lewis N, Kasirajan V. Heart Transplantation Outcomes in Patients With Hepatitis C Virus Infection: Potential Impact of Newer Antiviral Treatments After Transplantation. Fed Pract 2017; 34:S40-S48. [PMID: 30766309 PMCID: PMC6375473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
This study found significant improvements in heart transplant outcomes and survival in patients with hepatitis C virus.
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Affiliation(s)
- Mohammed Quader
- , and are surgeons in the division of cardiothoracic surgery, and is a statistician, all at Virginia Commonwealth University. is a cardiologist; and Dr. Quader, Dr. Katlaps, and Dr. Kasirajan are surgeons, all at McGuire Richmond VAMC in Virginia
| | - Luke G Wolfe
- , and are surgeons in the division of cardiothoracic surgery, and is a statistician, all at Virginia Commonwealth University. is a cardiologist; and Dr. Quader, Dr. Katlaps, and Dr. Kasirajan are surgeons, all at McGuire Richmond VAMC in Virginia
| | - Gundars Katlaps
- , and are surgeons in the division of cardiothoracic surgery, and is a statistician, all at Virginia Commonwealth University. is a cardiologist; and Dr. Quader, Dr. Katlaps, and Dr. Kasirajan are surgeons, all at McGuire Richmond VAMC in Virginia
| | - Neil Lewis
- , and are surgeons in the division of cardiothoracic surgery, and is a statistician, all at Virginia Commonwealth University. is a cardiologist; and Dr. Quader, Dr. Katlaps, and Dr. Kasirajan are surgeons, all at McGuire Richmond VAMC in Virginia
| | - Vigneshwar Kasirajan
- , and are surgeons in the division of cardiothoracic surgery, and is a statistician, all at Virginia Commonwealth University. is a cardiologist; and Dr. Quader, Dr. Katlaps, and Dr. Kasirajan are surgeons, all at McGuire Richmond VAMC in Virginia
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Toshikuni N. Therapy with Direct-Acting Antiviral Agents for Hepatitis C-Related Liver Cirrhosis. Gut Liver 2017; 11:335-348. [PMID: 27840363 PMCID: PMC5417775 DOI: 10.5009/gnl15458] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Revised: 10/27/2015] [Accepted: 12/11/2015] [Indexed: 12/23/2022] Open
Abstract
Chronic hepatitis C virus (HCV) infection may eventually lead to liver cirrhosis (LC), a condition associated with a high risk of liver failure and hepatocellular carcinoma. Although interferon (IFN)-based therapy has made substantial contributions to the management of HCV-infected patients, this therapy has limitations for LC patients in terms of eligibility, tolerability, relatively low and high rates of sustained virological response (SVR), and serious adverse events. Therapy with newly developed direct-acting antiviral agents (DAAs) can overcome these limitations in IFN-based therapy. Recent phase 3 trials have demonstrated that DAA therapy achieved high SVR rates (more than 90% for genotype 1; 80% to 90% for genotype 2; 60% to 70% for genotype 3) for compensated LC patients, with high tolerability and relatively low rates of serious adverse events. Furthermore, trials have suggested that DAA therapy can be used for the treatment of decompensated LC patients as well as pretransplant and posttransplant LC patients. In this article, we review the current status of DAA therapy for HCV-related LC patients.
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17
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Yoshida EM, Kwo P, Agarwal K, Duvoux C, Durand F, Peck-Radosavljevic M, Lilly L, Willems B, Vargas H, Kumar P, Brown Jr. RS, Horsmans Y, De-Oertel S, Arterburn S, Dvory-Sobol H, Brainard DM, McHutchison JG, Terrault N, Rizzetto M, Müllhaupt B. Persistence of Virologic Response after Liver Transplant in Hepatitis C Patients Treated with Ledipasvir / Sofosbuvir Plus Ribavirin Pretransplant. Ann Hepatol 2017; 16:375-381. [DOI: 10.5604/01.3001.0009.8592] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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18
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Donato MF, Morelli C, Romagnoli R, Invernizzi F, Mazzarelli C, Iemmolo RM, Montalbano M, Lenci I, Bhoori S, Pieri G, Berardi S, Caraceni P, Martini S. Prevention of hepatitis C recurrence by bridging sofosbuvir/ribavirin from pre- to post-liver transplant: a real-life strategy. Liver Int 2017; 37:678-683. [PMID: 27865034 DOI: 10.1111/liv.13322] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2016] [Accepted: 11/12/2016] [Indexed: 12/22/2022]
Abstract
BACKGROUND & AIMS Hepatitis C virus (HCV) re-infection following liver transplant (LT) is associated with reduced graft and patient survival. Before transplant, Sofosbuvir/Ribavirin (SOF/R) treatment prevents recurrent HCV in 96% of those patients achieving viral suppression for at least 4 weeks before transplant. We evaluated whether a bridging SOF-regimen from pre- to post-transplant is safe and effective to prevent HCV recurrence in those patients with less than 4 weeks of HCV-RNA undetectability at the time of transplant. METHODS From July 2014 SOF/R was given in 233 waitlisted HCV cirrhotics with/without hepatocellular carcinoma (HCC) within an Italian Compassionate Program. One hundred patients were transplanted and 31 patients (31%) treated with SOF/R bridging therapy were studied. RESULTS Liver transplant indication in bridge subgroup was HCC in 22 and decompensated cirrhosis in 9. HCV-genotype was 1/4 in 18 patients. SOF 400 mg/day and R (median dosage 800 mg/day) were given for a median of 35 days before LT. At transplant time, 19 patients were still HCV-RNA positive (median HCV-RNA 58 IU/mL). One recipient had a virological breakthrough at week 4 post-transplant; one died, on treatment, 1-month post-transplant for sepsis and 29/31 achieved a 12-week sustained virological response (94%). Acute cellular rejection occurred in three recipients. On September 2016, 30 recipients (97%) were alive with a median follow-up of 18 months (range 13-25). CONCLUSIONS In patients with suboptimal virological response at LT, a bridging SOF/R regimen helps avoiding post-transplant graft reinfection.
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Affiliation(s)
- Maria Francesca Donato
- Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Cristina Morelli
- U.O. Medicina Interna e delle Insufficienze d'Organo-Azienda Ospedaliera-Universitaria, Policlinico S. Orsola-Malpighi di Bologna, Bologna, Italy
| | - Renato Romagnoli
- Liver Transplantation Center, General Surgery Unit 2U, AOU Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Federica Invernizzi
- Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Chiara Mazzarelli
- Hepatology Unit and Liver Transplantation Surgery, Niguarda Hospital, Milan, Italy
| | - Rosa Maria Iemmolo
- Liver and Multivisceral Transplant Center, Azienda Ospedaliero-Universitaria di Modena, Modena, Italy
| | - Marzia Montalbano
- Infectious Diseases and General Surgery, National Institute for Infectious Diseases Spallanzani, Rome, Italy
| | - Ilaria Lenci
- Gastroenterology Unit and Experimental Medicine and Surgery, University of Tor Vergata, Rome, Italy
| | - Sherrie Bhoori
- Surgery and Liver Transplantation Unit, IRCCS National Institute of Cancer, Milan, Italy
| | - Giulia Pieri
- Division of Hepatology, IRCCS AO San Martino IST, Genova, Italy
| | - Sonia Berardi
- U.O. Medicina Interna e delle Insufficienze d'Organo-Azienda Ospedaliera-Universitaria, Policlinico S. Orsola-Malpighi di Bologna, Bologna, Italy
| | - Paolo Caraceni
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Silvia Martini
- Liver Transplantation Center, Gastrohepatology Unit, AOU Città della Salute e della Scienza di Torino, Turin, Italy
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van Tilborg M, Maan R, van der Meer AJ, de Knegt RJ. Interferon-free antiviral therapy for chronic hepatitis C among patients in the liver transplant setting. Best Pract Res Clin Gastroenterol 2017. [PMID: 28624110 DOI: 10.1016/j.bpg.2017.04.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Chronic hepatitis C (HCV) infection remains a major public health problem with many infected individuals worldwide. The revolutionary discovery of highly effective direct-acting antivirals (DAAs) makes chronic HCV infection a curable disease, even in patients with advanced liver disease. Liver function may improve shortly after initiation of antiviral therapy in patients on the waiting list and could even obviate the need for transplantation. However, whether these short term benefits also result in a favorable prognosis on the long-term remains to be seen and this fuels the discussion whether DAAs should be used prior to liver transplantation in all patients. Following liver transplantation, DAA treatment is also highly effective so that postponing antiviral treatment to the post-transplant setting may be better for certain patients. Furthermore, the discussion whether HCV positive organ donors should be used now viral eradication is achieved in almost all patients has regained interest.
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Affiliation(s)
| | - Raoel Maan
- Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
| | | | - Robert J de Knegt
- Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
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20
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Favorable Outcomes of Chinese HCV-Related Cirrhotic Patients with Sustained Virological Response after Pegylated Interferon Plus Ribavirin Treatment. BIOMED RESEARCH INTERNATIONAL 2017; 2017:8061091. [PMID: 28232944 PMCID: PMC5292367 DOI: 10.1155/2017/8061091] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Revised: 12/08/2016] [Accepted: 01/04/2017] [Indexed: 02/07/2023]
Abstract
Few studies have conducted follow-up investigations of the clinical course in HCV-related cirrhotic patients who achieved a sustained virological response (SVR) with pegylated interferon plus ribavirin treatment (PegIFN + RBV). We investigated the clinical course and laboratory data in a prospective cohort study enrolling HCV-related cirrhotic patients who received PegIFN + RBV between August 2008 and July 2013 in China. Complete blood counts, liver function tests, and HCV-RNA were serially examined. Liver-related complications were recorded. To detect hepatocellular carcinoma (HCC), alpha-fetoprotein assays, and ultrasound scans were repeated at 6-month intervals. Twenty-five patients were enrolled, including 8 patients with decompensation events before treatment. Eighteen patients achieved SVR with a mean follow-up period of 25.78 months. During the follow-up period, only one patient exhibited HCV-RNA positivity and no decompensation events were detected, but 4 patients developed HCC after SVR. APRI decreased more in patients with SVR than in patients with non-SVR (median, -1.33 versus 0.86, P < 0.001). The albumin levels and platelet counts significantly increased during the follow-up period after SVR (44.27 ± 4.09 versus 42.63 ± 4.37, P = 0.037 and 173.89 ± 87.36 versus 160.11 ± 77.97, P = 0.047). These data indicated that HCV-related cirrhotic patients with SVR after PegIFN + RBV may have a favorable clinical course and improvements in laboratory data. Moreover, HCC should be monitored.
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Gambato M, Caro-Pérez N, González P, Cañete N, Mariño Z, Lens S, Bonacci M, Bartres C, Sánchez-Tapias JM, Carrión JA, Forns X, Juan M, Pérez-del-Pulgar S, Londoño MC. Neutrophil and Monocyte Function in Patients with Chronic Hepatitis C Undergoing Antiviral Therapy with Regimens Containing Protease Inhibitors with and without Interferon. PLoS One 2016; 11:e0166631. [PMID: 27861593 PMCID: PMC5115763 DOI: 10.1371/journal.pone.0166631] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Accepted: 11/01/2016] [Indexed: 01/16/2023] Open
Abstract
Real-life data showed an increased incidence of bacterial infections in patients with advanced liver disease receiving a protease inhibitor (PI)-containing antiviral regimen against hepatitis C (HCV). However, the causes of this event are unknown. We hypothesized that PIs might impair innate immune responses through the inhibition of proteases participating in the anti-bacterial functions of neutrophils and monocytes. The aims of the study were to assess phagocytic and oxidative burst capacity in neutrophils and monocytes obtained from patients receiving a PI containing-antiviral regimen, and to determine cytokine secretion after neutrophil stimulation with flagellin. Forty patients with chronic HCV (80% with cirrhosis) were enrolled in the study, 28 received triple therapy (Group A) with pegylated-interferon and ribavirin for 4 weeks followed by the addition of a PI (telaprevir, boceprevir or simeprevir), and 12 patients received an interferon-free regimen (Group B) with simeprevir and sofosbuvir. Phagocytosis and oxidative burst capacity were analyzed by flow cytometry at baseline, week 4, and week 8 of therapy. In neutrophils from Group A patients, oxidative burst rate and oxidative enzymatic activity per cell significantly decreased throughout the study period (p = 0.014 and p = 0.010, respectively). Pairwise comparisons showed a decrease between baseline and week 4 and 8 of therapy. No differences were observed after the introduction of the PI. The oxidative enzymatic activity per cell in monocytes significantly decrease during the study period (p = 0.042) due to a decrease from baseline to week 8 of therapy (p = 0.037) in patients from Group A. None of these findings were observed in Group B patients. Cytokine secretion did not significantly change during the study in both groups. In conclusion, our data suggest that the use interferon (rather than the PI) has a deleterious effect on neutrophil and monocyte phagocytic and oxidative burst capacity in this cohort of patients with HCV-related advanced liver fibrosis.
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Affiliation(s)
- Martina Gambato
- Liver Unit, IDIBAPS and CIBEREHD, Hospital Clínic Barcelona, Barcelona, Spain
| | - Noelia Caro-Pérez
- Liver Unit, IDIBAPS and CIBEREHD, Hospital Clínic Barcelona, Barcelona, Spain
| | - Patricia González
- Liver Unit, IDIBAPS and CIBEREHD, Hospital Clínic Barcelona, Barcelona, Spain
| | - Nuria Cañete
- Liver Unit, Gastroenterology Department, Hospital del Mar, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | - Zoe Mariño
- Liver Unit, IDIBAPS and CIBEREHD, Hospital Clínic Barcelona, Barcelona, Spain
| | - Sabela Lens
- Liver Unit, IDIBAPS and CIBEREHD, Hospital Clínic Barcelona, Barcelona, Spain
| | - Martín Bonacci
- Liver Unit, IDIBAPS and CIBEREHD, Hospital Clínic Barcelona, Barcelona, Spain
| | - Concepció Bartres
- Liver Unit, IDIBAPS and CIBEREHD, Hospital Clínic Barcelona, Barcelona, Spain
| | | | - José A. Carrión
- Liver Unit, Gastroenterology Department, Hospital del Mar, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | - Xavier Forns
- Liver Unit, IDIBAPS and CIBEREHD, Hospital Clínic Barcelona, Barcelona, Spain
| | - Manel Juan
- Servei d’Immunologia, Hospital Clínic Barcelona, Barcelona, Spain
| | | | - María-Carlota Londoño
- Liver Unit, IDIBAPS and CIBEREHD, Hospital Clínic Barcelona, Barcelona, Spain
- * E-mail:
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22
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Graziadei I, Zoller H, Fickert P, Schneeberger S, Finkenstedt A, Peck-Radosavljevic M, Müller H, Kohl C, Sperner-Unterweger B, Eschertzhuber S, Hofer H, Öfner D, Tilg H, Vogel W, Trauner M, Berlakovich G. Indications for liver transplantation in adults : Recommendations of the Austrian Society for Gastroenterology and Hepatology (ÖGGH) in cooperation with the Austrian Society for Transplantation, Transfusion and Genetics (ATX). Wien Klin Wochenschr 2016; 128:679-690. [PMID: 27590261 PMCID: PMC5052293 DOI: 10.1007/s00508-016-1046-1] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Accepted: 05/30/2016] [Indexed: 02/06/2023]
Abstract
Liver transplantation has emerged as an established and well-accepted therapeutic option for patients with acute and chronic liver failure and hepatocellular carcinoma. The disproportion between recipients and donors is still an ongoing problem that has only been solved partially over the last centuries. For several patients no life-saving organs can be distributed. Therefore, objective and internationally established recommendations regarding indication and organ allocation are imperative. The aim of this article is to establish evidence-based recommendations regarding the evaluation and assessment of adult candidates for liver transplantation. This publication is the first Austrian consensus paper issued and approved by the Austrian Society of Gastroenterology and Hepatology in cooperation with the Austrian Society of Transplantation, Infusion and Genetics.
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Affiliation(s)
- Ivo Graziadei
- Department of Internal Medicine, Academic Teaching Hospital Hall i.T., Milserstraße 10, 6060, Hall i.T., Austria. .,Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria.
| | - Heinz Zoller
- Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria
| | - Peter Fickert
- Department of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
| | - Stefan Schneeberger
- Department of Visceral, Transplant and Thorax Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Armin Finkenstedt
- Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria
| | - Markus Peck-Radosavljevic
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Helmut Müller
- Department of Transplant Surgery, Medical University of Graz, Graz, Austria
| | - Claudia Kohl
- Department of Psychiatry, Medical University of Innsbruck, Innsbruck, Austria
| | | | - Stephan Eschertzhuber
- Department of Anesthesiology and Intensive Care Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Harald Hofer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Dietmar Öfner
- Department of Visceral, Transplant and Thorax Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Herbert Tilg
- Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, Austria
| | - Wolfgang Vogel
- Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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EXP CLIN TRANSPLANTExp Clin Transplant 2016; 14. [DOI: 10.6002/ect.2015.0284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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24
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Song ATW, Sobesky R, Vinaixa C, Dumortier J, Radenne S, Durand F, Calmus Y, Rousseau G, Latournerie M, Feray C, Delvart V, Roche B, Haim-Boukobza S, Roque-Afonso AM, Castaing D, Abdala E, D’Albuquerque LAC, Duclos-Vallée JC, Berenguer M, Samuel D. Predictive factors for survival and score application in liver retransplantation for hepatitis C recurrence. World J Gastroenterol 2016; 22:4547-4558. [PMID: 27182164 PMCID: PMC4858636 DOI: 10.3748/wjg.v22.i18.4547] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Accepted: 01/18/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To identify risk factors associated with survival in patients retransplanted for hepatitis C virus (HCV) recurrence and to apply a survival score to this population.
METHODS: We retrospectively identified 108 patients retransplanted for HCV recurrence in eight European liver transplantation centers (seven in France, one in Spain). Data collection comprised clinical and laboratory variables, including virological and antiviral treatment data. We then analyzed the factors associated with survival in this population. A recently published score that predicts survival in retransplantation in patients with hepatitis C was applied. Because there are currently no uniform recommendations regarding selection of the best candidates for retransplantation in this setting, we also described the clinical characteristics of 164 patients not retransplanted, with F3, F4, or fibrosing cholestatic hepatitis (FCH) post-first graft presenting with hepatic decompensation.
RESULTS: Overall retransplantation patient survival rates were 55%, 47%, and 43% at 3, 5, and 10 years, respectively. Patients who were retransplanted for advanced cirrhosis had survival rates of 59%, 52%, and 49% at 3, 5, and 10 years, while those retransplanted for FCH had survival rates of 34%, 29%, and 11%, respectively. Under multivariate analysis, and adjusting for the center effect and the occurrence of FCH, factors associated with better survival after retransplantation were: negative HCV viremia before retransplantation, antiviral therapy after retransplantation, non-genotype 1, a Model for End-stage Liver Disease (MELD) score < 25 when replaced on the waiting list, and a retransplantation donor age < 60 years. Although the numbers were small, in the context of the new antivirals era, we showed that outcomes in patients who underwent retransplantation with undetectable HCV viremia did not depend on donor age and MELD score. The Andrés score was applied to 102 patients for whom all score variables were available, producing a mean score of 43.4 (SD = 6.6). Survival rates after the date of the first decompensation post-first liver transplantation (LT1) in the liver retransplantation (reLT) group (94 patients decompensated) at 3, 5, and 10 years were 62%, 59%, and 51%, respectively, among 78 retransplanted individuals with advanced cirrhosis, and 42%, 32%, and 16% among 16 retransplanted individuals with FCH. In the non-reLT group with hepatic decompensation, survival rates were 27%, 18%, and 9% at 3, 5, and 10 years, respectively (P < 0.0001). Compared with non-retransplanted patients, retransplanted patients were younger at LT1 (mean age 48 ± 8 years compared to 53 ± 9 years in the no reLT group, P < 0.0001), less likely to have human immunodeficiency virus (HIV) co-infection (4% vs 14% among no reLT patients, P = 0.005), more likely to have received corticosteroid bolus therapy after LT1 (25% in reLT vs 12% in the no reLT group, P = 0.01), and more likely to have presented with sustained virological response (SVR) after the first transplantation (20% in the reLT group vs 7% in the no reLT group, P = 0.028).
CONCLUSION: Antiviral therapy before and after retransplantation had a substantial impact on survival in the context of retransplantation for HCV recurrence, and with the new direct-acting antivirals now available, outcomes should be even better in the future.
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Al-hamoudi WK. Management of hepatitis c genotype 4 in the liver transplant setting. Saudi J Gastroenterol 2016; 22:173-82. [PMID: 27184634 PMCID: PMC4898085 DOI: 10.4103/1319-3767.182453] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2015] [Accepted: 08/17/2015] [Indexed: 12/20/2022] Open
Abstract
End-stage liver disease secondary to hepatitis C virus (HCV) infection is the major indication for orthotopic liver transplantation (OLT) worldwide. The percentage of HCV patients infected with genotype 4 (G4) among recipients of OLT varies depending on geographic location. In the Middle East, including Saudi Arabia, G4 infection is the most common genotype among transplant recipients. Due to the low prevalence of HCV-G4 in Europe and the United States, this genotype has not been adequately studied in prospective trials evaluating treatment outcomes and remains the least studied variant. The aim of this review is to summarize the natural history and treatment outcome of HCV-G4 following liver transplantation, with particular attention to new HCV therapies. This review incorporates all published studies and abstracts including HCV-G4 patients.
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Affiliation(s)
- Waleed K. Al-hamoudi
- Department of Medicine, Gastroenterology Unit, College of Medicine, Liver Disease Research Center, King Saud University, Riyadh, Saudi Arabia
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26
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Reau N, Fried MW, Nelson DR, Brown RS, Everson GT, Gordon SC, Jacobson IM, Lim JK, Pockros PJ, Reddy KR, Sherman KE. HCV Council--critical appraisal of data: recommendations for clinical practice in a rapidly evolving therapeutic landscape. Liver Int 2016; 36:488-502. [PMID: 26509462 PMCID: PMC5063106 DOI: 10.1111/liv.12993] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Accepted: 10/21/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS HCV Council 2014, like its predecessor HCV Council 2011, assembled leading clinicians and researchers in the field of hepatitis C to critically evaluate current data regarding best practices for managing patients with chronic hepatitis C virus (HCV). METHODS Clinical practice statements were developed that reflect the areas of potential controversy with high clinical impact. Faculty members were responsible for reviewing the literature to support or reject these statements. After a review and comprehensive discussion of the data, the HCV Council faculty voted on the nature of the evidence and the level of support for each statement. RESULTS The results of the detailed analysis with expert opinion are summarized in this article. CONCLUSION Numerous questions regarding optimal management of certain populations and clinical scenarios remain unanswered. The discussion in the article provides a summary of evidenced-based expert opinion that may help guide clinicians as additional information is developed.
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Affiliation(s)
- Nancy Reau
- Rush University Medical CenterChicagoILUSA
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27
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Trotter JF. Current Issues in Liver Transplantation. Gastroenterol Hepatol (N Y) 2016; 12:214-219. [PMID: 27231452 PMCID: PMC4872851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
The state of liver transplantation continues to evolve. This article focuses on 3 separate yet important issues within this field. First, there is a proposal to change the allocation of donor livers in the United States. The fundamental premise of this proposal is to equalize access to donor livers across the country. To accomplish this goal, the proposal is to increase the geographic area of liver allocation. As might be expected, there is a great deal of controversy surrounding the possibility of a major change in liver allocation and distribution. A second area of interest, and perhaps the most important therapeutic breakthrough in the field of hepatology, is the introduction of direct-acting antiviral agents against hepatitis C virus (HCV) infection. With cure rates up to 100%, an increasing proportion of liver transplant candidates and recipients are being cured of HCV infection with therapies that have minimal side effects. Consequently, the impact of HCV infection on patient and graft survival will likely improve substantially over the next few years. Finally, this article reviews the role of donor-specific antibodies (DSAs) in antibody-mediated rejection. Long recognized as an important factor in graft survival in renal transplantation, DSAs have recently been shown to be a strong predictor of graft and patient survival in liver transplantation. However, the importance of DSAs in liver transplantation is uncertain, in large part due to the absence of proven therapies.
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Affiliation(s)
- James F Trotter
- Dr Trotter is the medical director of liver transplantation at Baylor University Medical Center in Dallas, Texas
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28
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Modi AA, Nazario H, Trotter JF, Gautam M, Weinstein J, Mantry P, Barnes M, Habib A, McAfee J, Teachenor O, Tujague L, Gonzalez S. Safety and efficacy of simeprevir plus sofosbuvir with or without ribavirin in patients with decompensated genotype 1 hepatitis C cirrhosis. Liver Transpl 2016; 22:281-6. [PMID: 26335142 DOI: 10.1002/lt.24324] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Revised: 08/25/2015] [Accepted: 08/26/2015] [Indexed: 12/13/2022]
Abstract
Combination antiviral therapy involving sofosbuvir (SOF) and simeprevir (SIM) is a treatment option in patients with genotype 1 chronic hepatitis C; however, the safety of this regimen in patients with decompensated cirrhosis is not established. Data from a combined treatment cohort of 2 large hepatology referral centers were evaluated to assess for safety and efficacy of SIM plus SOF with or without ribavirin (RBV) in patients with Child B or C cirrhosis. All (n = 42) patients included in the analysis had Child B (n = 35) or C (n = 7) cirrhosis and received 400 mg daily of SOF plus 150 mg daily of SIM, with (n = 7) or without (n = 35) RBV, for 12 weeks. Of the 42 patients in this cohort, 31 (74%) were male, 22 (52%) had failed prior treatments, and 28 (67%) were genotype 1a. Prior decompensating events included encephalopathy (57%), fluid overload (88%), or variceal hemorrhage (24%). Median Model for End-Stage Liver Disease score was 12 (range, 6-25). Treatment was well tolerated overall with more than one-half (57%) reporting no adverse events. In those reporting adverse events, the most common were fatigue (n = 6), insomnia (n = 4), headache (n = 5), nausea (n = 4), and grade 1 rash (n = 1). One patient developed chemical pancreatitis that did not require treatment discontinuation. Three of 7 patients who received RBV developed anemia, with 2 requiring blood transfusions and 1 requiring a dose reduction. No episodes of decompensation requiring hospitalization or deaths occurred on treatment. Of 42 patients, 38 (90%) patients had negative viral load at end of treatment (EOT), and 31 of 42 patients (74%) achieved sustained virological response 12 weeks after EOT; 10 of 10 patients (100%) with HCV genotype 1b achieved sustained virological response for 12 weeks (SVR12). In conclusion, SOF plus SIM was very well tolerated in patients with advanced Child B/C decompensated cirrhosis. Overall, 74% of patients achieved SVR12; 100% of patients with genotype 1b decompensated cirrhosis achieved SVR12.
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Affiliation(s)
- Apurva A Modi
- Liver Consultants of Texas, Baylor Simmons Transplant Center, Fort Worth, TX
| | - Hector Nazario
- Liver Institute, Methodist Dallas Medical Center, Dallas, TX
| | - James F Trotter
- Liver Consultants of Texas, Baylor Simmons Transplant Center, Fort Worth, TX
| | - Manjushree Gautam
- Liver Consultants of Texas, Baylor Simmons Transplant Center, Fort Worth, TX
| | | | - Parvez Mantry
- Liver Institute, Methodist Dallas Medical Center, Dallas, TX
| | - Maisha Barnes
- Liver Institute, Methodist Dallas Medical Center, Dallas, TX
| | - Adil Habib
- Liver Institute, Methodist Dallas Medical Center, Dallas, TX
| | - Jean McAfee
- Liver Consultants of Texas, Baylor Simmons Transplant Center, Fort Worth, TX
| | - Olga Teachenor
- Liver Institute, Methodist Dallas Medical Center, Dallas, TX
| | - Lauren Tujague
- Liver Institute, Methodist Dallas Medical Center, Dallas, TX
| | - Stevan Gonzalez
- Liver Consultants of Texas, Baylor Simmons Transplant Center, Fort Worth, TX
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29
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O’Shea D, Law J, Egli A, Douglas D, Lund G, Forester S, Lambert J, Law M, Burton D, Tyrrell D, Houghton M, Humar A, Kneteman N. Prevention of hepatitis C virus infection using a broad cross-neutralizing monoclonal antibody (AR4A) and epigallocatechin gallate. Liver Transpl 2016; 22:324-32. [PMID: 26389583 PMCID: PMC4769112 DOI: 10.1002/lt.24344] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2015] [Accepted: 09/01/2015] [Indexed: 01/13/2023]
Abstract
The anti-hepatitis C virus (HCV) activity of a novel monoclonal antibody (mAb; AR4A) and epigallocatechin gallate (EGCG) were studied in vitro using a HCV cell culture system and in vivo using a humanized liver mouse model capable of supporting HCV replication. Alone, both exhibit reliable cross-genotype HCV inhibition in vitro, and combination therapy completely prevented HCV infection. In vitro AR4A mAb (alone and combined with EGCG) robustly protects against the establishment of HCV genotype 1a infection. EGCG alone fails to reliably protect against an HCV challenge. In conclusion, AR4A mAb represents a safe and efficacious broadly neutralizing antibody against HCV applicable to strategies to safely prevent HCV reinfection following liver transplantation, and it lends further support to the concept of HCV vaccine development. The poor bioavailability of EGCG limits HCV antiviral activity in vitro.
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Affiliation(s)
- D. O’Shea
- Transplant Infectious Diseases, Alberta Transplant Institute, Department of Medicine, University of Alberta,Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada,To whom correspondence should be addressed: Daire O’Shea, Consultant in Infectious Diseases, Regional Infectious Diseases Unit, Crewe Road, Edinburgh EH4 2XU, Scotland, UK, Tel: +441315372862, Fax: +441315372878,
| | - J Law
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada
| | - A Egli
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada
| | - D Douglas
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada
| | - G Lund
- KMT Hepatech, University of Alberta, Edmonton, Alberta, Canada
| | - S Forester
- Dept. of Food Science, Pennsylvania State University, PA
| | - J Lambert
- Dept. of Food Science, Pennsylvania State University, PA
| | - M Law
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla CA 92037, USA
| | - D.R. Burton
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla CA 92037, USA,Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA
| | - D.L.J. Tyrrell
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada
| | - M. Houghton
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada
| | - A. Humar
- Toronto General Hospital, University Health Network, Multi-Organ Transplant Program Toronto, Ontario, Canada
| | - N Kneteman
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada,Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
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30
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31
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Deming P, Martin MT, Chan J, Dilworth TJ, El-Lababidi R, Love BL, Mohammad RA, Nguyen A, Spooner LM, Wortman SB. Therapeutic Advances in HCV Genotype 1 Infection: Insights from the Society of Infectious Diseases Pharmacists. Pharmacotherapy 2016; 36:203-17. [PMID: 26846728 DOI: 10.1002/phar.1700] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Hepatitis C virus (HCV) is the most common blood-borne infection in the United States. The high morbidity and mortality due to untreated infection have prompted updated screening recommendations that now include one-time HCV screening for all patients born between 1945 and 1965, in addition to risk factor-based screening. Current guidelines recommend treatment for all patients with chronic HCV. Treatment for HCV genotype 1 has evolved dramatically since the approval of the direct-acting antivirals. The approval of ledipasvir-sofosbuvir, ombitasvir-paritaprevir-ritonavir and dasabuvir, and simeprevir with sofosbuvir has dramatically altered the treatment landscape. High sustained virologic response (SVR) rates favor treatment, yet access to care poses a challenge for patients and providers. Current and emerging data with new therapies indicate high SVR rates in treatment-naïve and treatment-experienced patients, including patients with cirrhosis and in other special populations. Additional data suggest the addition of ribavirin can decrease treatment duration without compromising SVR rates. Resistance is an increasing area of interest in HCV, with baseline mutations identified and the potential for the development of resistance-associate variants in patients undergoing treatment. Due to the rapid evolution of HCV treatment, pharmacists should address challenges and play an integral role in agent selection, dosing, drug interaction screening, adverse effect monitoring, and the coordination of treatment. Clinical application of the latest information will reduce patient risk and improve outcomes.
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Affiliation(s)
- Paulina Deming
- Department of Pharmacy Practice, University of New Mexico College of Pharmacy, Albuquerque, New Mexico
| | - Michelle T Martin
- Department of Pharmacy Practice, University of Illinois at Chicago College of Pharmacy, University of Illinois Hospital and Health Sciences System, Chicago, Illinois
| | - Juliana Chan
- Colleges of Pharmacy and Medicine, University of Illinois at Chicago, Chicago, Illinois.,Gastroenterology/Hepatology, Illinois Department of Corrections Hepatology Telemedicine, Sections of Hepatology, Digestive Diseases and Nutrition, University of Illinois Hospital & Health Sciences Center, Chicago, Illinois
| | - Thomas J Dilworth
- Department of Pharmacy, Wheaton Franciscan Healthcare - St. Francis, Milwaukee, Wisconsin.,Center for AIDS Intervention Research, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Rania El-Lababidi
- Pharmacy Education and Training, Department of Pharmacy Services, Cleveland Clinic Abu Dhabi, Abu Dhabi, UAE
| | - Bryan L Love
- Clinical Pharmacy and Outcomes Sciences, South Carolina College of Pharmacy, Columbia, South Carolina
| | - Rima A Mohammad
- Department of Clinical, Social, and Administrative Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan.,University of Michigan Health System, Ann Arbor, Michigan
| | - Amy Nguyen
- Gallup Indian Medical Center, Gallup, New Mexico
| | - Linda M Spooner
- Pharmacy Practice, School of Pharmacy Worcester/Manchester, MCPHS University, Worcester, Massachusetts.,Infectious Diseases, Saint Vincent Hospital, Worcester, Massachusetts
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33
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Ascha MS, Ascha ML, Hanouneh IA. Management of immunosuppressant agents following liver transplantation: Less is more. World J Hepatol 2016; 8:148-161. [PMID: 26839639 PMCID: PMC4724578 DOI: 10.4254/wjh.v8.i3.148] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Revised: 09/12/2015] [Accepted: 01/07/2016] [Indexed: 02/06/2023] Open
Abstract
Immunosuppression in organ transplantation was revolutionary for its time, but technological and population changes cast new light on its use. First, metabolic syndrome (MS) is increasing as a public health issue, concomitantly increasing as an issue for post-orthotopic liver transplantation patients; yet the medications regularly used for immunosuppression contribute to dysfunctional metabolism. Current mainstay immunosuppression involves the use of calcineurin inhibitors; these are potent, but nonspecifically disrupt intracellular signaling in such a way as to exacerbate the impact of MS on the liver. Second, the impacts of acute cellular rejection and malignancy are reviewed in terms of their severity and possible interactions with immunosuppressive medications. Finally, immunosuppressive agents must be considered in terms of new developments in hepatitis C virus treatment, which undercut what used to be inevitable viral recurrence. Overall, while traditional immunosuppressive agents remain the most used, the specific side-effect profiles of all immunosuppressants must be weighed in light of the individual patient.
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34
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Ferrarese A, Zanetto A, Gambato M, Bortoluzzi I, Nadal E, Germani G, Senzolo M, Burra P, Russo FP. Liver transplantation for viral hepatitis in 2015. World J Gastroenterol 2016; 22:1570-1581. [PMID: 26819523 PMCID: PMC4721989 DOI: 10.3748/wjg.v22.i4.1570] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Accepted: 11/19/2015] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation (LT) is a life-saving treatment for patients with end-stage liver disease and for patients with liver cell cancer related to liver disease. Acute and chronic liver diseases related to hepatitis viruses are between the main indications for liver transplantation. The risk of viral reinfection after transplantation is the main limiting factor in these indications. Before the availability of antiviral prophylaxis, hepatitis B virus (HBV) recurrence was universal in patients who were HBV DNA-positive before transplantation. The natural history of recurrent HBV was accelerated by immunosuppression, and it progressed rapidly to graft failure and death. Introduction of post-transplant prophylaxis with immunoglobulin alone first, and associated to antiviral drugs later, drastically reduced HBV recurrence, resulting in excellent long-term outcomes. On the contrary, recurrence of hepatitis C is the main cause of graft loss in most transplant programs. Overall, patient and graft survival after LT for hepatitis C virus (HCV)-associated cirrhosis is inferior compared with other indications. However, successful pretransplant or post transplant antiviral therapy has been associated with increased graft and overall survival. Until recently, the combination of pegylated interferon and ribavirin was the standard of care for the treatment of patients with chronic hepatitis C. Highly active antiviral compounds have been developed over the past decade, thanks to new in vitro systems to study HCV entry, replication, assembly, and release.
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35
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Infectious Considerations in the Pre-Transplant Evaluation of Cirrhotic Patients Awaiting Orthotopic Liver Transplantation. Curr Infect Dis Rep 2016; 18:4. [PMID: 26743200 DOI: 10.1007/s11908-015-0514-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The incidence of end-stage liver disease (ESLD) is increasing and many of these patients may be considered for orthotopic liver transplantation. As patients with ESLD are at risk of a number of infections, infectious disease physicians should be aware of the management of these infections in order to provide optimal patient care and ensure transplantation success. We present a review of the literature pertaining to infectious disease considerations in the liver transplant candidate. It highlights several topics with recent developments including the management of hepatitis C virus infection prior to transplantation, treatment of hepatitis B virus infection, colonization and infection with multidrug resistant organisms, and management of spontaneous bacterial peritonitis.
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36
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Saeed N, Gurakar A. Tackling HCV-3 in Asia: Breakthroughs for Efficient and Cost-effective Treatment Strategies. Euroasian J Hepatogastroenterol 2016; 6:35-42. [PMID: 29201722 PMCID: PMC5578556 DOI: 10.5005/jp-journals-10018-1163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Accepted: 10/18/2015] [Indexed: 11/23/2022] Open
Abstract
Hepatitis C virus (HCV) is known to cause chronic hepatitis C, and its sequelae of cirrhosis and hepatocellular carcinoma. Hepatitis C genotype 3 (HCV-3) in particular is notorious for causing accelerated liver fibrosis, cardiovascular, and metabolic effects, thus increasing morbidity and mortality. It is the commonest variant in Asian countries like India and Pakistan. It is also one of the hardest-to-treat genotypes, especially among treatment-experienced and cirrhotic patients. Due to limited health care affordability and accessibility in these areas, many patients remain untreated. Until recently, the established therapy for HCV had been a combination of pegylated interferon + ribavirin. However, it was only effective in about half of patients and had severe adverse effects; hence a more efficacious option needed to be found. Recent advances have led to the development of sofosbuvir, an NS5B inhibitor that is fast becoming the standard of care, in combination with other novel drugs. It was initially marketed at $1,000 per pill, a cost that was too high for most. Thus, it has not been utilized as a global therapy as yet. Formulation of effective interferon-free regimens is a huge milestone, and awareness needs to be raised regarding these new highly effective options in both the physician and the patient population. This article discusses the newest drugs and combinations that have been developed in the fight against HCV-3, as a treatment outline for HCV-3-dominant areas. It also highlights recent breakthroughs in cost reductions of these drugs and the effort to make them globally accessible. HOW TO CITE THIS ARTICLE Saeed N, Gurakar A. Tackling HCV-3 in Asia: Breakthroughs for Efficient and Cost-effective Treatment Strategies. Euroasian J Hepato-Gastroenterol 2016;6(1):35-42.
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Affiliation(s)
- Naba Saeed
- Department of Transplant Hepatology, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Ahmet Gurakar
- Department of Transplant Hepatology, Johns Hopkins University School of Medicine, Division of Gastroenterology and Hepatology, Baltimore Maryland, USA
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37
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Saxena V, Terrault N. Current Management of Hepatitis C Virus: Regimens for Peri-Liver Transplant Patients. Clin Liver Dis 2015; 19:669-88, vi. [PMID: 26466655 PMCID: PMC8115933 DOI: 10.1016/j.cld.2015.06.007] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Chronic hepatitis C virus (HCV) infection currently remains the leading indication for liver transplant in the United States. However, recurrent HCV infection after transplant is universal in those who enter transplant with viremia resulting in reduced posttransplant graft and patient survival rates, caused in large part by progressive recurrent HCV disease. Therefore, successful treatment of HCV in the peri-transplant period, either before or after transplant, is paramount in ensuring improved posttransplant outcomes. This article reviews the experience to date treating HCV in wait-listed patients and liver transplant recipients and the unique challenges encountered when treating this population.
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Affiliation(s)
- Varun Saxena
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Norah Terrault
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
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38
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Saab S, Greenberg A, Li E, Bau SN, Durazo F, El-Kabany M, Han S, Busuttil RW. Sofosbuvir and simeprevir is effective for recurrent hepatitis C in liver transplant recipients. Liver Int 2015; 35:2442-7. [PMID: 25913321 DOI: 10.1111/liv.12856] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Accepted: 04/21/2015] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS Hepatitis C is the most common indication for liver transplantation (LT). Recurrent infection is universal and can lead to progressive liver disease. Widespread use of interferon-based therapy has been limited by intolerability and adverse effects. METHODS We retrospectively evaluated the safety, tolerability, and efficacy of sofosbuvir and simeprevir in the treatment of recurrent hepatitis C in adult (age >18) LT recipients. RESULTS Seventy-six percent of the recipients were male and the mean age [±standard deviation (SD)] was 61 (±6.0) years. The mean time (±SD) from LT to treatment initiation was 71.8 (±77.1) months. Of the 26 patients with viral levels measured 4 weeks after starting antiviral therapy, 58% were undetectable. At the end of therapy, viral load was undetectable in all transplant recipients. The 12 week sustained viral response (SVR) was 93%. All recipients were able to complete therapy and no patients required growth factors of blood product transfusion during treatment. No patient required drug interruption of their immunosuppressant therapy. CONCLUSION The use of sofosbuvir and simeprevir is efficacious, safe, and tolerable and should be considered in LT recipients with recurrent HCV who are candidates for antiviral therapy.
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Affiliation(s)
- Sammy Saab
- Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.,Department of Surgery, University of California, Los Angeles, Los Angeles, CA, USA
| | - Adam Greenberg
- Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Edwin Li
- Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Sherona Ngashea Bau
- Department of Surgery, University of California, Los Angeles, Los Angeles, CA, USA
| | - Francisco Durazo
- Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.,Department of Surgery, University of California, Los Angeles, Los Angeles, CA, USA
| | - Mohammed El-Kabany
- Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.,Department of Surgery, University of California, Los Angeles, Los Angeles, CA, USA
| | - Steven Han
- Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.,Department of Surgery, University of California, Los Angeles, Los Angeles, CA, USA
| | - Ronald W Busuttil
- Department of Surgery, University of California, Los Angeles, Los Angeles, CA, USA
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Righi E, Londero A, Carnelutti A, Baccarani U, Bassetti M. Impact of new treatment options for hepatitis C virus infection in liver transplantation. World J Gastroenterol 2015; 21:10760-75. [PMID: 26478668 PMCID: PMC4600578 DOI: 10.3748/wjg.v21.i38.10760] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Revised: 07/12/2015] [Accepted: 09/15/2015] [Indexed: 02/06/2023] Open
Abstract
Liver transplant candidates and recipients with hepatitis C virus (HCV)-related liver disease greatly benefit from an effective antiviral therapy. The achievement of a sustained virological response before transplantation can prevent the recurrence of post-transplant HCV disease that occurs universally and correlates with enhanced progression to graft cirrhosis. Previous standard-of-care regimens (e.g., pegylated-interferon plus ribavirin with or without first generation protease inhibitors, boceprevir and telaprevir) displayed suboptimal results and poor tolerance in liver transplant recipients. A new class of potent direct-acting antiviral agents (DAA) characterized by all-oral regimens with minimal side effects has been approved and included in the recent guidelines for the treatment of liver transplant recipients with recurrent HCV disease. Association of sofosbuvir with ribavirin and/or ledipasvir is recommended in liver transplant recipients and patients with decompensated cirrhosis. Other regimens include simeprevir, daclatasvir, and combination of other DAA. Possible interactions should be monitored, especially in coinfected human immunodeficiency virus/HCV patients receiving antiretrovirals.
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Coilly A, Dumortier J, Botta-Fridlund D, Latournerie M, Leroy V, Pageaux GP, Agostini H, Giostra E, Moreno C, Roche B, Antonini TM, Guillaud O, Lebray P, Radenne S, Saouli AC, Calmus Y, Alric L, Debette-Gratien M, De Ledinghen V, Durand F, Duvoux C, Samuel D, Duclos-Vallée JC. Multicenter Experience with Boceprevir or Telaprevir to Treat Hepatitis C Recurrence after Liver Transplantation: When Present Becomes Past, What Lessons for Future? PLoS One 2015; 10:e0138091. [PMID: 26394142 PMCID: PMC4578772 DOI: 10.1371/journal.pone.0138091] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Accepted: 08/25/2015] [Indexed: 12/20/2022] Open
Abstract
Background and aims First generation protease inhibitors (PI) with peg-interferon (PEG-IFN) and ribavirin (RBV) have been the only therapy available for hepatitis C virus (HCV) genotype 1 infection in most countries for 3 years. We have investigated the efficacy and tolerance of this triple therapy in transplanted patients experiencing a recurrence of HCV infection on the liver graft. Patients This cohort study enrolled 81 liver transplant patients (Male: 76%, mean age: 55.8±9.7 years) with severe HCV recurrence (F3 or F4: n = 34 (42%), treatment experienced: n = 44 (54%)), treated with boceprevir (n = 36; 44%) or telaprevir (n = 45; 56%). We assessed the percentages of patients with sustained virological responses 24 weeks after therapy (SVR24), and safety. Results The SVR24 rate was 47% (telaprevir: 42%; boceprevir: 53%, P = ns). At baseline, a normal bilirubin level (p = 0.0145) and albumin level >35g/L (p = 0.0372) and an initial RBV dosage of ≥800 mg/day (p = 0.0033) predicted SVR24. During treatment, achieving an early virological response after 12 weeks was the strongest independent factor to predict SVR24 (p<0.0001). A premature discontinuation of anti-HCV therapy due to a serious adverse event (SAE) was observed in 22 patients (27%). Hematological toxicity, infections and deaths were observed in 95%, 28% and 7% of patients, respectively. A history of post-LT antiviral therapy and thrombocytopenia (<50G/L) during treatment were both independent predictors of the occurrence of infections or SAE (p = 0.0169 and p = 0.011). Conclusions The use of first generation PI after liver transplantation enabled an SVR24 rate of 47% in genotype 1 patients, but induced a high rate of SAE. The identification of predictive factors for a response to treatment, and the occurrence of SAE, have enabled us to establish limits for the use of this anti-HCV therapy in the transplant setting.
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Affiliation(s)
- Audrey Coilly
- AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Villejuif, F-94800, France, Université Paris-Sud, UMR-S 785, Villejuif, F-94800, France, Inserm, Unité 785, Villejuif, F-94800, France, Hepatinov, Villejuif, F-94800, France
| | - Jérôme Dumortier
- Department of Digestive Diseases, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon, France
| | - Danielle Botta-Fridlund
- Assistance Publique—Hôpitaux de Marseille, Centre Hospitalo-Universitaire Conception, Service d'Hépato-Gastro-Entérologie, Marseille, France
| | | | - Vincent Leroy
- Service d’hépato-gastro-entérologie, hôpital A.-Michallon, 38700, La Tronche, France
| | - Georges-Philippe Pageaux
- Fédération médico-chirurgicale des maladies de l’appareil digestif, hôpital Saint-Eloi, 34295, Montpellier, France
| | - Hélène Agostini
- AP-HP, Hôpital Bicêtre, Unité de recherche clinique Paris-Sud, Kremlin-Bicêtre, France
| | - Emiliano Giostra
- Department of Gastroenterology and Hepatology, Geneva University Hospital, Rue Gabrielle-Perret-Gentil 4, 1211, Geneva, 14, Switzerland
| | - Christophe Moreno
- Liver unit, Department of Gastroenterology, Hepatopancreatology and Digestive oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
| | - Bruno Roche
- AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Villejuif, F-94800, France, Université Paris-Sud, UMR-S 785, Villejuif, F-94800, France, Inserm, Unité 785, Villejuif, F-94800, France, Hepatinov, Villejuif, F-94800, France
| | - Teresa Maria Antonini
- AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Villejuif, F-94800, France, Université Paris-Sud, UMR-S 785, Villejuif, F-94800, France, Inserm, Unité 785, Villejuif, F-94800, France, Hepatinov, Villejuif, F-94800, France
| | - Olivier Guillaud
- Department of Digestive Diseases, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon, France
| | - Pascal Lebray
- Assistance Publique Hôpitaux de Paris (AP-HP), Groupe Hospitalier Pitié-Salpêtrière, Paris, France
| | - Sylvie Radenne
- Service d’hépatologie, HCL, hôpital de la Croix-Rousse, 69205, Lyon, France
| | - Anne-Catherine Saouli
- Hepato-Bilio-Pancreatic Surgery and Liver Transplantation Center, Université de Strasbourg, Strasbourg, France
| | - Yvon Calmus
- Department of Hepatobiliary and Liver Transplantation Surgery, Hopital Saint Antoine, Assistance publique-Hopitaux de Paris, 184 rue du Faubourg Saint-Antoine, 75012, Paris Cedex, France
| | - Laurent Alric
- Internal medecine-Digestive department UMR 152 IRD Toulouse 3 University, Toulouse, France
| | - Maryline Debette-Gratien
- Service d'Hépato-gastroentérologie, CHU de Limoges, 2 avenue Martin-Luther-King, 87042, Limoges, France, Inserm UMR 1092, Faculté de médecine de Limoges, Université de Limoges, Limoges, France
| | | | - François Durand
- Service d’hépatologie, hôpital Beaujon, AP–HP, 92118, Clichy, France
| | - Christophe Duvoux
- Service d’hépatologie, hôpital Henri-Mondor, AP–HP, 94000, Créteil, France
| | - Didier Samuel
- AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Villejuif, F-94800, France, Université Paris-Sud, UMR-S 785, Villejuif, F-94800, France, Inserm, Unité 785, Villejuif, F-94800, France, Hepatinov, Villejuif, F-94800, France
| | - Jean-Charles Duclos-Vallée
- AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Villejuif, F-94800, France, Université Paris-Sud, UMR-S 785, Villejuif, F-94800, France, Inserm, Unité 785, Villejuif, F-94800, France, Hepatinov, Villejuif, F-94800, France
- * E-mail:
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Abstract
Hepatitis C-related cirrhosis is the main indication for liver transplantation. In the absence of viral eradication, viral recurrence leads to recurrent HCV disease and progression to advanced graft disease in many recipients, particularly those transplanted with subobtimal grafts. Viral eradication is associated with improved outcome whether used pre- or post-transplantation. In the new era of interferon-free regimes, this is now safe and feasible in most transplant candidates and transplant recipients. There are questions that remain unanswered, such as defining the point of no return where clinical improvement does not follow viral eradication or management of treatment failures.
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Affiliation(s)
- Marina Berenguer
- La Fe University Hospital and Ciberehd, Department of digestive diseases, Hepatology and Liver Transplantation Unit, Avinguda de Fernando Abril Martorell, n(o) 106, Valencia 46026, Spain.
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Abstract
PURPOSE OF REVIEW Hepatitis C virus (HCV) infection remains the leading indication for liver transplant, and viral eradication prior to liver transplant to prevent disease recurrence has traditionally been challenging because of the poor tolerability and efficacy of available therapies. However, with the recent introduction of potent interferon (IFN)-free direct acting antiviral regimens, viral eradication prior to liver transplant is now possible. RECENT FINDINGS Although data are limited, several proof of concept studies have now shown high rates of safety and efficacy in patients with compensated as well as mild-to-moderately decompensated cirrhosis. Although, treatment on the liver transplant waiting list can safely prevent postliver transplant recurrence in selected patients, the ideal regimen and treatment duration have yet to be determined. SUMMARY Although IFN-free therapies represent a tremendous advance in our ability to cure this previously difficult to treat population, additional data on the safety of these regimens, particularly in patients with severely decompensated cirrhosis, the consequences of virologic failure and the impact of viral eradication on short- and long-term liver function are urgently needed.
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Belli LS, Romagnoli R, Nardi A, Marianelli T, Donato F, Corradini SG, Iemmolo RM, Morelli C, Pasulo L, Rendina M, De Martin E, Ponziani FR, Volpes R, Strazzabosco M, Angelico M. Recipient female gender is a risk factor for graft loss after liver transplantation for chronic hepatitis C: Evidence from the prospective Liver Match cohort. Dig Liver Dis 2015; 47:689-94. [PMID: 26055490 DOI: 10.1016/j.dld.2015.04.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2015] [Revised: 03/28/2015] [Accepted: 04/08/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Female gender has been reported to be a risk factor for graft loss after liver transplantation for hepatitis C virus (HCV)-related cirrhosis but evidence is limited to retrospective studies. AIMS To investigate the impact of recipient gender and donor/recipient gender mismatch on graft outcome. METHODS We performed a survival analysis of a cohort of 1530 first adult transplants enrolled consecutively in Italy between 2007 and 2009 and followed prospectively. After excluding possible confounding factors (fulminant hepatitis, human immunodeficiency virus co-infection, non-viremic anti-HCV positive subjects), a total of 1394 transplant recipients (604 HCV-positive and 790 HCV-negative) were included. RESULTS Five-year graft survival was significantly reduced in HCV-positive patients (64% vs 76%, p=0.0002); Cox analysis identified recipient female gender (HR=1.44, 95% CI 1.03-2.00, p=0.0319), Mayo clinic End stage Liver Disease score (every 10 units, HR=1.25, 95% CI 1.03-1.50; p=0.022), portal thrombosis (HR=2.40, 95% CI 1.20-4.79, p=0.0134) and donor age (every 10 years, HR=1.14, 95% CI 1.05-1.24, p=0.0024) as independent determinants of graft loss. All additional mortality observed among female recipients was attributable to severe HCV recurrence. CONCLUSIONS This study unequivocally shows that recipient female gender unfavourably affects the outcome of HCV-infected liver grafts.
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Affiliation(s)
- Luca Saverio Belli
- Department of Hepatology and Gastroenterology, Niguarda Hospital, Milan, Italy.
| | - Renato Romagnoli
- Liver Transplant Center, Azienda Ospedaliera Città della Salute e della Scienza, University of Turin, Italy
| | - Alessandra Nardi
- Department of Mathematics, Tor Vergata University Hospital, Rome, Italy
| | - Tania Marianelli
- Department of Mathematics, Tor Vergata University Hospital, Rome, Italy
| | - Francesca Donato
- Division of Digestive Diseases, "Maggiore" University Hospital, Milan, Italy
| | | | | | | | - Luisa Pasulo
- Gastroenterology and Transplant Hepatology, San Giovanni XXIII Hospital, Bergamo, Italy
| | - Maria Rendina
- Department of Emergency and Organ Transplantation, University Hospital, Bari, Italy
| | | | | | | | - Mario Strazzabosco
- Digestive Disease Section, University Hospital Milano Bicocca and Yale University Center, New Haven, USA
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Khullar V, Firpi RJ. Hepatitis C cirrhosis: New perspectives for diagnosis and treatment. World J Hepatol 2015; 7:1843-1855. [PMID: 26207166 PMCID: PMC4506942 DOI: 10.4254/wjh.v7.i14.1843] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Revised: 02/24/2015] [Accepted: 07/08/2015] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis C infection is the leading cause of chronic liver disease, cirrhosis, hepatocellular carcinoma as well as the primary indication for liver transplantation in the United States. Despite recent advances in drugs for the treatment of hepatitis C, predictive models estimate the incidence of cirrhosis due to hepatitis C infection will to continue to rise for the next two decades. There is currently an immense interest in the treatment of patients with fibrosis and early-stage cirrhosis as treatment can lead to decrease in the rates of decompensated cirrhosis, hepatocellular carcinoma and need for liver transplantation in these patients. The goal of this paper is to provide clinicians and health care professionals further information about the treatment of patients with hepatitis C infection and cirrhosis. Additionally, the paper focuses on the disease burden, epidemiology, diagnosis and the disease course from infection to treatment. We provide an overview of multiple studies for the treatment of chronic hepatitis C infection that have included patients with cirrhosis. We also discuss the advantages and disadvantages of treatment in cirrhotic patients and focus on the most up to date guidelines available for treatment.
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Brown RS. Universal Hepatitis C Eradication Prior to Liver Transplantation: We Can Do It, but Should We? Am J Transplant 2015; 15:1741-2. [PMID: 26086299 DOI: 10.1111/ajt.13319] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Revised: 03/09/2015] [Accepted: 03/16/2015] [Indexed: 01/25/2023]
Affiliation(s)
- R S Brown
- Center for Liver Disease and Transplantation, Columbia University College of Physicians and Surgeons, New York, NY
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Abstract
The first liver transplantation (LT) was performed by Thomas E Starzl five decades ago, and yet it remains the only therapeutic option offering gold standard treatment for end-stage liver disease (ESLD) and acute liver failure (ALF) and certain early-stage liver tumors. Post-liver transplantation survival has also dramatically improved over the last few decades despite increasing donor and recipient age and more frequent use of marginal organs to overcome the organ shortage. Currently, the overall 1 year survival following LT in the United States is reported as 85 to 90%, while the 10 years survival rate is ~50% (http://www.unos.org). The improvements are mainly due to progress in surgical techniques, postoperative intensive care, and the advent of new immunosuppressive agents. There are a number of factors that influence the outcomes prior to transplantation. Since 2002, the model for end-stage liver disease (MELD) score has been considered a predicting variable. It has been used to prioritize patients on the transplant waiting list and is currently the standard method used to assess severity in all etiologies of cirrhosis. Hepatocellular carcinoma (HCC) is the most common standard MELD exception because the MELD does not necessarily reflect the medical urgency of patients with HCC. The criteria for candidates with HCC for receiving LT have evolved over the past decade. Now, patients with HCC who do not meet the traditional Milan (MC) or UCSF criteria for LT often undergo downstaging therapy I an effort to shrink the tumor size. The shortage of donor organs is a universal problem. In some countries, the development of a deceased organ donation program has been prevented due to socioeconomic, cultural, legal and other factors. Due to the shortage of cadaveric donors, several innovative techniques have been developed to expand the organ donor pool, such as split liver grafts, marginal- or extended-criteria donors, live donor liver transplantation (LDLT), and the use of organs donated after cardiac death. Herein, we briefly summarize recent advances in knowledge related to LT. We also report common causes of death after liver transplant, including the recurrence of hepatitis C virus (HCV) and its management, and coronary artery disease (CAD), including the role of the cardiac calcium score in identifying occult CAD. HOW TO CITE THIS ARTICLE Dogan S, Gurakar A. Liver Transplantation Update: 2014. Euroasian J Hepato-Gastroenterol 2015;5(2):98-106.
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Affiliation(s)
- Serkan Dogan
- Department of Gastroenterology, Johns Hopkins School of Medicine, Maryland, United States
| | - Ahmet Gurakar
- Division of Gastroenterology and Hepatology, Johns Hopkins School of Medicine, Maryland, United States
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Cavalcante LN, Lyra AC. Predictive factors associated with hepatitis C antiviral therapy response. World J Hepatol 2015; 7:1617-31. [PMID: 26140082 PMCID: PMC4483544 DOI: 10.4254/wjh.v7.i12.1617] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 12/16/2014] [Accepted: 05/05/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection may lead to significant liver injury, and viral, environmental, host, immunologic and genetic factors may contribute to the differences in the disease expression and treatment response. In the early 2000s, dual therapy using a combination of pegylated interferon plus ribavirin (PR) became the standard of care for HCV treatment. In this PR era, predictive factors of therapy response related to virus and host have been identified. In 2010/2011, therapeutic regimens for HCV genotype 1 patients were modified, and the addition of NS3/4a protease inhibitors (boceprevir or telaprevir) to dual therapy increased the effectiveness and chances of sustained virologic response (SVR). Nevertheless, the first-generation triple therapy is associated with many adverse events, some of which are serious and associated with death, particularly in cirrhotic patients. This led to the need to identify viral and host predictive factors that might influence the SVR rate to triple therapy and avoid unnecessary exposure to these drugs. Over the past four years, hepatitis C treatment has been rapidly changing with the development of new therapies and other developments. Currently, with the more recent generations of pangenotipic antiviral therapies, there have been higher sustained virologic rates, and prognostic factors may not have the same importance and strength as before. Nonetheless, some variables may still be consistent with the low rates of non-response with regimens that include sofosbuvir, daclatasvir and ledipasvir. In this manuscript, we review the predictive factors of therapy response across the different treatment regimens over the last decade including the new antiviral drugs.
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Affiliation(s)
- Lourianne Nascimento Cavalcante
- Lourianne Nascimento Cavalcante, André Castro Lyra, Hospital Sao Rafael - Gastro-Hepatology Service, Salvador, Bahia 41253-190, Brazil
| | - André Castro Lyra
- Lourianne Nascimento Cavalcante, André Castro Lyra, Hospital Sao Rafael - Gastro-Hepatology Service, Salvador, Bahia 41253-190, Brazil
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Filipec Kanizaj T, Kunac N. Hepatitis C: New challenges in liver transplantation. World J Gastroenterol 2015; 21:5768-77. [PMID: 26019441 PMCID: PMC4438011 DOI: 10.3748/wjg.v21.i19.5768] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Revised: 02/28/2015] [Accepted: 04/17/2015] [Indexed: 02/06/2023] Open
Abstract
In an era of great achievements in liver transplantation, hepatitis C viral infection (HCV) remains an unsolved problem. As a leading indication for liver transplantation in Western countries, HCV poses a significant burden both before and after transplantation. Post-transplant disease recurrence occurs in nearly all patients with detectable pretransplant viremia, compromising the lifesaving significance of transplantation. Many factors involving the donor, recipient and virus have been evaluated throughout the literature, although few have been fully elucidated and implemented in actual clinical practice. Antiviral therapy has been recognized as a cornerstone of HCV infection control; however, experience and success are diminished following transplantation in a challenging cohort of patients with liver cirrhosis. Current therapeutic protocols surpass those used previously, both in sustained viral response and side-effect profile. In this article we review the most relevant and contemporary scientific evidence regarding hepatitis C infection and liver transplantation, with special attention dedicated to novel, more efficient and safer antiviral regimens.
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Abstract
PURPOSE OF REVIEW To review and highlight recent literature regarding the medical management of adult patients undergoing liver transplantation. RECENT FINDINGS The addition of serum sodium concentration to the model for end-stage liver disease (MELD) score more accurately predicts 90-day waitlist mortality. Predictors of waitlist mortality and posttransplant survival include lower albumin and the presence of ascites, varices, and encephalopathy, as well as more nontraditional predictors such as older age, obesity, frailty, and sarcopenia. Indications for liver transplantation are evolving with the advent of effective therapy for hepatitis C and the increased prevalence of nonalcoholic steatohepatitis. Disparities persist in the current allocation system, including geographic variation and MELD inflation for hepatocellular carcinoma. Share 35 allows for broader regional sharing of organs for patients with the highest need, without detrimental effects on waitlist mortality or survival. Everolimus is a recently approved option for posttransplant immunosuppression that spares renal function. SUMMARY The MELD score has enabled the liver transplant community to equitably allocate organs. Recent literature has focused on the limitations of the MELD score and the disparities inherent in the current system. The next steps for liver transplantation will be to develop strategies to further optimize waitlist prioritization and organ allocation.
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